The goal of the proposed SNRP at UHM-John A. Burns School of Medicine (JABSOM) is to develop a critical mass of neuroscientists who will focus their research efforts on health problems that are highly prevalent in Hawai'i, particularly among the under-represented minority populations. These neuroscientists are trained in a variety of disciplines and will contribute to and collaborate on five interdisciplinary projects proposed in this application. The scientific issues to be explored in the proposed research program will involve the understanding of neurotoxic effects of the major drugs of abuse in Hawaii [i.e. methamphetamine (Meth) and marijuana] and to learn whether prenatal methamphetamine exposure might affect neonatal brain development. The problems of Meth and marijuana abuse affect the underserved minorities, specifically Pacific islanders, and Asians, in Hawai'i more than other populations. Furthermore, although the population infected with HIV is relatively smaller compared to some major metropolitan areas, the rising infection rate among the Asian Pacific Islanders is a concern to the local Department of Health. Therefore, we will also explore possible mechanisms of brain injury in HIV. To achieve this goal, the following are the scientific objectives: 1) To evaluate changes in brain function in individuals with substance-dependence (specifically with methamphetamine and with marijuana);2) to evaluate possible brain changes in neonates with prenatal methamphetamine exposure;3) to develop in vivo markers of oxidative stress and determine whether changes in these markers are related to neurotoxicity in HIV subjects with or without Meth abuse. We also propose the following programmatic objectives: 1) to build strong interdisciplinary teams of researchers to study brain-related changes associated with substance abuse (especially methamphetamine and marijuana, which are highly prevalent in Hawaii) and with HIV/AIDS;2) to provide mentoring to junior investigators and graduate students, including medical students, residents and fellows, for their career development;3) to provide a forum for inter-disciplinary learning through bi-monthly research seminars and bi-monthly journal clubs. These scientific and programmatic objectives will be achieved through the four interdisciplinary projects, an administrative-clinical-training core and a technical core proposed in this application. PROJECT 1 PI: Edward Chronicle, Ph.D. DESCRIPTION (provided by applicant): The acute use of cannabis by humans has well-known effects on cognition, emotion, motor behavior and perception, via the action of THC at CB1 receptors in the central nervous system. The long-term consequences of cannabis use are less well understood. It is possible that changes in the brains of cannabis users have not hitherto been detected because appropriately sensitive and targeted methods have not been used. We propose to employ two powerful neuroscientific tools to search for subtle deficits in brain function in cannabis users. First, transcranial magnetic stimulation (TMS) protocols will be used to probe the functional status of motor and visual cortices in chronic users. We hypothesize that active frequent cannabis users will show changes in performance reflective of decreased excitability and a gain of inhibitory function, and that these changes will correlate with measures of estimated cumulative THC intake. Second, the technique of interleaving TMS with BOLD signal acquisition in fMRI will allow assessment of the extent and magnitude of motor system response to a localized and calibrated cortical stimulus. We hypothesize that a reduction in excitability is likely to result in a decrease in the extent of the induced BOLD signal in active frequent users, which will again be correlated with measures of cumulative THC intake. Third, we will extend previous BOLD-fMRI studies by employing a battery of attentional, memory and motor tasks. We hypothesize that the extent and/or magnitude of activation will decrease for attentional and motor tasks but increase for two memory tasks. Fourth, we will examine the effects of acute and chronic administration of tetrahydrocannabinol (THC) and other CB1 agonists, and of THC withdrawal, on responses to forepaw sensory in the rat brain, using a high-field animal imaging system. The combination of TMS/fMRI in humans and fMRI in an animal model will allow us to understand how attentional, motor, memory and motor systems may be dysregulated in active frequent cannabis users, giving rise to functional changes. As cannabis is widely used in the United States and elsewhere, and has potential medical benefits for some populations (e.g. glaucoma, HIV, cancer), it is a matter of utmost concern to public health to determine the consequences of frequent cannabis use for the brain. We thus envisage that this project will inform issues of public policy.